Multi-dimensional image reconstruction

ABSTRACT

Apparatus for radiation based imaging of a non-homogenous target area having distinguishable regions therein, comprises: an imaging unit configured to obtain radiation intensity data from a target region in the spatial dimensions and at least one other dimension, and an image four-dimension analysis unit analyzes the intensity data in the spatial dimension and said at least one other dimension in order to map the distinguishable regions. The system typically detects rates of change over time in signals from radiopharmaceuticals and uses the rates of change to identify the tissues. In a preferred embodiment, two or more radiopharmaceuticals are used, the results of one being used as a constraint on the other.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.11/656,548 filed Jan. 23, 2007, which is a continuation of U.S. patentapplication Ser. No. 11/034,007 filed Jan. 13, 2005, now U.S. Pat. No.7,176,466, which claims the benefit of priority of U.S. ProvisionalPatent Application No. 60/535,830 filed Jan. 13, 2004. The contents ofthe above applications are all incorporated by reference as if fully setforth herein in their entirety.

FIELD AND BACKGROUND OF THE INVENTION

The present invention relates to multi-dimensional image reconstructionand, more particularly, but not exclusively to such image reconstructionbased on a diffuse radioactive source or sources.

Radiological imaging is generally carried out on a living target, whichof course means a mix of tissues in close proximity, if not actuallyoverlapping. The general procedure is to feed the patient with one ormore radioactive markers prior to the imaging process. The radioactivemarkers are taken up by the digestive system and pass into thebloodstream. From the bloodstream the marker passes into the differenttissues at varying rates depending on the tissue type. Some tissuesabsorb markers faster than others and some tissues absorb certainmarkers faster than others. Furthermore certain tissues flush out themarkers faster than others, and again the rate of flushing out may alsodepend on the kind of marker being used.

As a result, radioactive marking in fact creates a dynamic system in thebody in which the relative darkness of a given tissue is related to atime factor. The radiologist knows that if he wants a good image of saythe liver following application of a given marker then he should wait acertain number of hours from application of the marker before taking theimage. Even so, the liver is not differentiated clearly from the othertissues.

Examples of radiopharmaceuticals include monoclonal antibodies or otheragents, e.g., fibrinogen or fluorodeoxyglucose, tagged with aradioactive isotope, e.g., 99Mtechnetium, 67gallium, 201thallium,111indium, 123iodine, 125iodine and 18fluorine, which may beadministered orally or intravenously. The radiopharmaceuticals aredesigned to concentrate in the area of a tumor, and the uptake of suchradiopharmaceuticals in the active part of a tumor, or other pathologiessuch as an inflammation, is higher and more rapid than in the tissuethat neighbors the tumor. Thereafter, aradiation-emission-measuring-probe, which may be configured forextracorporeal or intracorporeal use, is employed for locating theposition of the active area. Another application is the detection ofblood clots with radiopharmaceuticals such as ACUTECT from NycomedAmersham for the detection of newly formed thrombosis in veins, or clotsin arteries of the heart or brain, in an emergency or operating room.Yet other applications include radioimaging of myocardial infarct usingagents such as radioactive anti-myosin antibodies, radioimaging specificcell types using radioactively tagged molecules (also known as molecularimaging), etc.

The usual preferred emission for such applications is that of gammarays, which emission is in the energy range of approximately 11-511 KeV.Beta radiation and positrons may also be detected.

Radioactive-emission imaging is performed with aradioactive-emission-measuring detector, such as a room temperature,solid-state CdZnTe (CZT) detector, which is among the more promisingthat is currently available. It may be configured as a single-pixel or amulti-pixel detector, and may be obtained, for example, from eVProducts, a division of II-VI Corporation, Saxonburg Pa., 16056, or fromIMARAD IMAGING SYSTEMS LTD., of Rehovot, ISRAEL, 76124, www.imarad.com,or from another source. Alternatively, another solid-state detector suchas CdTe, HgI, Si, Ge, or the like, or a combination of a scintillationdetector (such as NaI(Tl), LSO, GSO, CsI, CaF, or the like) and aphotomultiplier, or another detector as known, may be used.

Considering the issue in greater detail, certain biological or chemicalsubstances such as targeted peptides, monoclonal antibodies and others,are used for tagging specific living molecules for diagnostic purposes.Ideally, these antibodies are specific to the desired type of cells,based on adhering only to specific molecular structures in which theantigene matching the antibody is highly expressed. The use of imagingdevices such as a nuclear gamma probe or a visual video probe can detectradiation emanating from taggants such as radionuclei or fluorescentdies that have been appended to the antibody before being delivered tothe living body. An example is a cancerous cell of a prostate tumor onwhose membrane there is an over expression of the Prostate SpecificMembrane Antigen (PSMA). When a monoclonal antibody (Mab) such asCapromab Pendetide (commercially available as ProstaScint manufacturedby Cytogen Corp.) is labeled with radioactive Indium (In 111) and issystemically delivered to the body, the Mab is carried by the bloodstream and upon reaching the prostate tissue, adheres to the PSMA. Thehigh energy radiation photons emitted by the radioactive Indium can bedetected using a nuclear camera, indicating the presence and thespecific location of the tumor.

Unfortunately, given the complexity of living organisms, in manyinstances the same antigen is also expressed in more than just thetissue under investigation. The antibody will thus also “paint”additional tissues such as infection areas, in addition to the tissue ofinterest. The radioactive readings taken from this additional tissuewill be falsely interpreted as tumor areas, reducing the specificity ofthe test being performed.

The ‘Target to Background’ ratio that characterizes every such antibodyfor a given target cell type is one of the major issues that determinethe ability to perform proper diagnosis, and guided procedures.

Since the uptake clearance of such a marker by the various tissues(target and background) varies over time, standard diagnosis protocolsusually recommend taking an image at the time at which the ratio ofTarget emission vs. Background emission is the highest.

In an experimental system tried out by researchers, two markers weresupplied to various patients and then images were taken at successiveintervals for each of the markers. Certain features in the target areasshowed up clearly in all images, other features were clear for allimages of one marker but faded in and faded out for the other marker,and yet other features faded in and out for both markers but atdifferent times. The researchers were able to use their knowledge of thebehaviors of the two markers with different tissues in order to identifythe features in the images.

The above system therefore relies on the knowledge of the researchers toput together information received from multiple images into anunderstanding of what the radio-imaging shows. In the general hospitalenvironment it is not possible to guarantee that the necessary expertiseis available, at least not for the amount of time that such a systemwould require.

There is thus a widely recognized need for, and it would be highlyadvantageous to have, a radiological imaging system devoid of the abovelimitations.

SUMMARY OF THE INVENTION

According to one aspect of the present invention there is providedapparatus for radiation based imaging and analysis of a non-homogenoustarget area having distinguishable regions therein, the apparatuscomprising:

-   -   an imaging unit configured to obtain radiation emission data        from said target region in the spatial dimensions and at least        one other dimension, and    -   an image multi-dimensional analysis unit associated with said        imaging unit for analyzing said obtained emission data in said        spatial dimensions and said at least one other dimension in        order to discern patterns across said dimensions.

According to a second aspect of the present invention there is providedapparatus for radiation based imaging of a non-homogenous target areahaving distinguishable regions therein, the apparatus comprising:

-   -   an imaging unit configured to obtain radiation emission data        from said target region in the spatial dimensions and a time        dimension, and    -   an image multi-dimensional analysis unit associated with said        imaging unit for analyzing said obtained emission data in said        spatial dimensions and said time dimension in order to discern        at least one property from a time profile of a marker in said        distinguishable regions of said target area.

According to a third aspect of the present invention there is providedapparatus for radiation based imaging and analysis of a target area, theapparatus comprising:

-   -   an imaging unit configured to obtain radiation emission data        from said target region in the spatial dimensions and at least        one other dimension, and    -   an image multi-dimensional analysis unit associated with said        imaging unit for analyzing said obtained emission data in said        spatial dimensions and said at least one other dimension in        order to discern patterns within a respective target region.

According to a fourth aspect of the present invention there is provideda method of radiation based imaging, comprising:

-   -   acquiring data;    -   reconstructing an image from said data;    -   automatically detecting at least one region, in said image; and    -   automatic controlling at least one of said acquiring and said        reconstructing to generate an improved image, based on said        detecting.

According to a fifth aspect of the present invention there is provided amethod for improved tomographic reconstruction of radiation intensities,comprising:

-   -   initially reconstructing at least one distinguishable region        from said radiation intensities    -   extracting parameters associated with different properties of        said reconstructed distinguishable region;    -   classifying said at least one reconstructed distinguishable        region by the extracted parameters associated therewith;    -   iteratively using the classification of said extracted        parameters to improve delimitation of said classified        reconstructed distinguishable region, thereby to improve        reconstruction thereof.

According to a sixth aspect of the present invention there is provided amethod of optimization of therapy of the human or animal body,comprising:

-   -   identifying a target region for said therapy;    -   applying to a patient at least one radioactive marker;    -   obtaining radiation emission data from said target region in the        spatial dimensions and at least one other dimension, and    -   analyzing said obtained emission data in spatial dimensions and        at least one other dimension in order to discern patterns across        said dimensions, thereby to characterize said target region, and    -   optimizing said therapy based on said characterization.

According to a seventh aspect of the present invention there is providedapparatus for multi-dimensional image reconstruction based on dataacquired from an imaging unit for obtaining radiation intensity datafrom a target region in the spatial dimensions and at least one otherdimension, the apparatus comprising:

-   -   an image four-dimension analysis unit configured to analyze said        obtained intensity data in said spatial dimension and said at        least one other dimension in order to map at least one        distinguishable region in terms of a property, said property        being that of at least one member of the group comprising a        tissue, a disease, a disease stage and a physiological process.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. The materials, methods, andexamples provided herein are illustrative only and not intended to belimiting.

Implementation of the method and system of the present inventioninvolves performing or completing certain selected tasks or stepsmanually, automatically, or a combination thereof. Moreover, accordingto actual instrumentation and equipment of preferred embodiments of themethod and system of the present invention, several selected steps couldbe implemented by hardware or by software on any operating system of anyfirmware or a combination thereof. For example, as hardware, selectedsteps of the invention could be implemented as a chip or a circuit. Assoftware, selected steps of the invention could be implemented as aplurality of software instructions being executed by a computer usingany suitable operating system. In any case, selected steps of the methodand system of the invention could be described as being performed by adata processor, such as a computing platform for executing a pluralityof instructions.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention is herein described, by way of example only, withreference to the accompanying drawings. With specific reference now tothe drawings in detail, it is stressed that the particulars shown are byway of example and for purposes of illustrative discussion of thepreferred embodiments of the present invention only, and are presentedin order to provide what is believed to be the most useful and readilyunderstood description of the principles and conceptual aspects of theinvention. In this regard, no attempt is made to show structural detailsof the invention in more detail than is necessary for a fundamentalunderstanding of the invention, the description taken with the drawingsmaking apparent to those skilled in the art how the several forms of theinvention may be embodied in practice.

In the drawings:

FIG. 1 is a simplified diagram showing a single detector detecting overa target region;

FIG. 2 is a simplified diagram showing two detector positions (notnecessarily simultaneously) allowing three-dimensional information to beobtained from a target region;

FIGS. 3A-3D show a series of four time absorption characteristics fordifferent radiopharmaceuticals within different tissues;

FIG. 4 is a simplified schematic diagram showing a device for driving animaging head and allowing control of the imaging head by the imageanalyzer device;

FIG. 5 is a simplified flow chart illustrating the image analysisprocess carried out by the analyzer in FIG. 4 in the case of a singlemarker;

FIGS. 6A-6D illustrate two sets of successive images of the same targetarea taken using two different markers respectively, according to apreferred embodiment of the present invention;

FIG. 7A is a simplified flow chart illustrating a procedure according toa preferred embodiment of the present invention using two or moremarkers for first of all identifying an organ and then secondlydetermining the presence or otherwise of a pathology within that organ;

FIG. 7B is a simplified flow chart showing a generalization of FIG. 7Afor the general case of two specific patterns;

FIG. 8 is a simplified flow chart illustrating a procedure according toa preferred embodiment of the present invention using two or moremarkers for identifying a region of low emissivity within a target areaand using that identification to control imaging resources to betterimage the identified region; and

FIGS. 9A-9D illustrate two sets of successive images of the same targetarea taken using two different markers, in a similar way to that shownin FIG. 6, except that this time the regions of interest are one insidethe other.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present embodiments comprise an apparatus and a method for radiationbased imaging of a non-homogenous target area having regions ofdifferent material or tissue type or pathology. The imaging usesmulti-dimensional data of the target area in order to distinguish thedifferent regions. Typically the multi-dimensional data involves time asone of the dimensions. A radioactive marker has particulartime-absorption characteristics which are specific for the differenttissues, and the imaging device is programmed to constrain its imagingto a particular characteristic.

The result is not merely an image which concentrates on the tissue ofinterest but also, because it is constrained to the tissue of interest,is able to concentrate imaging resources on that tissue and thus producea higher resolution image than the prior art systems which arecompletely tissue blind.

The principles and operation of a radiological imaging system accordingto the present invention may be better understood with reference to thedrawings and accompanying description.

Before explaining at least one embodiment of the invention in detail, itis to be understood that the invention is not limited in its applicationto the details of construction and the arrangement of the components setforth in the following description or illustrated in the drawings. Theinvention is capable of other embodiments or of being practiced orcarried out in various ways. Also, it is to be understood that thephraseology and terminology employed herein is for the purpose ofdescription and should not be regarded as limiting.

Reference is now made to FIG. 1, which illustrates a simple Geigercounter taking an image of a target according to the prior art. Geigercounter 10 is placed in association with target 12 and absorbs anyradioactive particles that come its way. In general the radioactiveparticles arriving at the Geiger counter arrive from somewhere withincone 14. The Geiger counter has no information as to the depth fromwhich the particle comes and cannot even distinguish between particlesarriving from different directions within the cone. Thus in principlethe prior art Geiger counter gives low resolution one dimensionalinformation.

If the counter is now moved to different positions over the surface ofthe target then the data from the different positions can be built upinto a low resolution two-dimensional image.

One way of increasing the resolution of the Geiger counter is to make itsmaller. Then the cone, whilst retaining the same geometry, gives higherresolution data.

The detector takes (y_(t))_(t=1) ^(T) samples to form a data set, whichwould typically be a two-dimensional image of the target from a givendirection.

Reference is now made to FIG. 2, which is a simplified diagram showinghow three-dimensional information can be obtained from the target. Partsthat are the same as in previous figures are given the same referencenumerals and are not referred to again except as necessary forunderstanding the present embodiment. A second Geiger counter 16 isplaced essentially at right angles to the first Geiger counter andobtains a similar kind of image to the first Geiger counter. However,since the two cones overlap, the images produced can be cross-correlatedto infer the presence of hot or cold radiation sources in threedimensions.

Reference is now made to FIG. 3, which is a sequence of graphsillustrating the different absorption characteristics for differenttissues of a given radioactive marker. Typical markers that may beconsidered are Thalium 201 and Technitium 99. FIG. 3 a indicates atypical absorption characteristic of thalium 201 for blood, thalium 201being a particularly good marker for blood. The marker is generallyabsorbed by the blood fairly rapidly following digestion and thengradually disappears as it is taken up by the various tissues and organsincluding the kidneys. Marker material from the tissues eventually findsits way back into the blood for excretion. That which is absorbed by thekidneys is excreted directly and not seen again.

FIGS. 3B, 3C and 3D show time absorption characteristics for technitium99 for different tissues, and it will be seen that the characteristic isgenerally curved but peaks at different times for the different tissues.

The principle on which the present embodiments are based is as follows:Considering the graphs in FIG. 3, it will be apparent that a regionbelonging to a single tissue will behave in a uniform manner as regardssignal intensity. That is to say, a given marker will be taken up andthen expelled at the same rate over a given tissue, whereas this ratewill be different for other tissues. If therefore a series of successiveimages are taken of the target and the images are analyzed region byregion for rates of change of intensity, a particular desired region canbe identified by virtue of having rates of change in intensity that fitwith a given characteristic. The regions are distinguishable in this wayeven if the region of interest is heavily overlapped with other regions.

Reference is now made to FIG. 4, which shows apparatus forradiation-based imaging of a non-homogenous target area. Apparatus 20comprises an imaging unit 22 which itself consists of a series of smallGeiger counters 24.1 . . . 24.n arranged on an imaging head. The imagingunit is controlled by motion controller 26 to take readings fromdifferent locations around the target area. Preferably, the motion ofthe imaging head is controlled by software via servo-motors. In additionthe motions, either of the individual Geiger counters or of groupings ofthe Geiger counters, is also controlled by software via servo-motors.

In a preferred embodiment, the signals received from the individualGeiger counters are summed to form a three-dimensional image of thetarget area. The skilled person will appreciate that the system couldalso be based on a two-dimensional image. In either case, the signalsare fed to an image analyzer 28, where the signals are analyzed to formimages.

In the preferred embodiments, the image analyzer is able to use themarker take up characteristics to compare successive images and identifyregions of particular interest, and then to concentrate imagingresources on those regions. That is to say the image analyzer is in factable to control further operation of the imager.

Reference is now made to FIG. 5, which is a simplified flow chartillustrating the image analysis process carried out by analyzer 28 inthe case of a single marker. Preferably a series of images of the sameviews are taken at different times, stage 30, and a three-dimensionaloverall image of the target is formed for each time. The analyzer thenanalyzes each of the three-dimensional overall images for localintensities at different locations around the target, stage 32. Thelocal intensities are noted and the same locations on the differentimages are superimposed in stage 34. From the superpositioning, localrates of change of intensity between the images may be obtained in stage36. The rates of change are compared with the pre-obtainedcharacteristics for the marker with the different tissues in stage 38,and the data are then constrained to those localities which conform tothe desired predetermined characteristics in stage 40. As a result theimaging process can be used to identify and concentrate on localities ofinterest and data from other localities can be jettisoned. Consequently,the image analysis is able to concentrate its resources on the tissuesof interest and a higher resolution final image can be produced.

It will be appreciated that in many cases two types of tissue may besuperimposed, of which only one of the tissues is of interest. In thiscase it is of equal importance both to exclude the one tissue that isnot of interest and to include the tissue that is of interest. It may bethat the best marker for one tissue may not be the best marker for theother tissue. The system as described with respect to FIGS. 4 and 5 maybe adapted to use with two or more markers, as exemplified in FIG. 6.Each marker produces a radioactive particle of different energy level,and therefore the data from the different markers can be collected andsummed separately to form different images. Mathematically the differentdata sets obtained from the different energy level signals may betreated as different dimensions of a multi-dimensional vector. For eachof the marker-images the appropriate characteristics are used toidentify the tissues of interest, and the results can be cross-checkedbetween the different markers. The different tissues can be mapped andthe image analysis can concentrate on the area of interest. As a resultthe system uses both time and particle energy as separate dimensions inaddition to the spatial dimensions in order to characterize or map thetissues.

As a result the image analysis unit is able to produce a final resulttreating the various tissue regions as separate entities. Furthermore,as the system is aware of the regions as entities it is able to furtherdirect the imaging process to concentrate on the regions of interest.

An example in which regions at least partially overlap is the heart.Generally, scans of the heart are interested in the muscular walls ofthe heart. Although the chambers of the heart are filled with blood, anysignal coming from the blood is in fact noise to this kind of scan. Itis therefore advantageous to carry out an imaging process which is ableto positively identify signals from the muscular heart walls and at thesame time exclude the blood.

Referring now to FIG. 6, and in a preferred embodiment, the patientingests two markers, thalium 201 and technetium 99. The first of theseis an effective blood marker and two successive thalium images are shownin FIGS. 6 a and 6 b, and the second is more effective at marking muscletissue and two successive images thereof are shown in FIGS. 6 c and 6 d.The heart is imaged at intervals chosen both for the characteristic forthalium 201 in blood and for the characteristic of technetium 99 inmuscle. The result is a series of images for each of the markers. Theseries for thalium 201 may be constrained to show the regions of bloodquite clearly, and to filter out other regions. In here a blood vesselis shown clearly in 6 a and more faintly in 6 b where the thalium hasmostly been flushed out. The series for technetium 99, FIGS. 6 c and 6 dshow muscle wall structures. The first of the two images apparentlyshows larger structures but in fact all that it is showing is that muchtechnetium has not yet been absorbed in the muscle. The second image 6 dmay therefore be used to constrain the first image 6 c to show only themuscle walls regions. The two series of images may then be superimposedto filter out from the technetium 99 images 6 c and 6 d anything thatappears strongly in the thalium images 6 a and 6 b. The filtering mayadditionally remove anything that appears strongly in both images ascoming from outside the region.

In the above example, two regions were of respectively positive andnegative interest, meaning one for concentrating on and the other forfiltering out. It will be appreciated that several regions or severaltissue types may be of positive interest or there may be any combinationof regions with just one being of positive interest. Alternatively allregions may be of positive interest but importance may be attached todiscriminating between the different signals from the different regions.

The system is able to use the mapping to generate an image comprisingthe different tissue regions as distinct entities. As a consequence ofthe mapping process, the system is able to be aware electronically ofthe different regions and thus control both the imaging head and theanalysis unit to concentrate their resources on specific regions. Theresult is greater resolution for the regions of interest.

The preferred embodiments may be used to expand the information obtainedfrom the markers, using either or both of examining the kinetics of themarkers over time and using several markers concurrently.

In order to increase the specificity of the test, additional secondsubstances (“secondary substances”), with reactivity andpharmaco-kinetics differing from those of the first substance can beused in order to enhance the differentiation between the differentpathologies, as explained above with respect to FIG. 6. The secondarysubstance, in this case thalium, ideally marks only a subset of thepopulation marked by the primary substance and does so at differentrates. Such a difference exists because of different affinity to variouscell types and different participation in metabolic reactions ofdifferent tissues. The difference is associated with the rate of markingand/or with the location of the marking.

Upon reading the radioactive signals emanating from the voxels stemmingfrom different substances at different time instances, it is possible tobuild for every voxel a multi dimensional data matrix Sjk whose elementsare intensity readings taken at instances K resulting from theinteraction of Substance J. Examination of every voxel of tissue in thismultidimensional space quantifies the temporal and specific reaction ofthe tissue to different substances and thus increases the probability ofspecific detection of different pathologies. Furthermore, standard imageprocessing techniques can be used in order to more accurately define thespatial location of different pathologies.

In addition to the method above, spatial properties that reflect typicalrelationships between neighboring voxels may also be a criteria andrepresented as part of the pattern of the tissue type.

Reference is now made to FIG. 7, which illustrates an additionalstatistical approach. In FIG. 7, an automatic algorithm based onexpected intensities may be used to determine if the entire organ orregion is diseased or non-diseased. Once it is possible to becometissue-aware, as explained above, then it is no longer necessary tocarry out such analysis on a voxel-by-voxel basis. Rather the system isable to determine where the organ lies say using a first marker and thena second marker may be imaged using the constraint of the organlocation, the second marker being able to locate the presence of thepathology.

Reference is now made to FIG. 8 which illustrates a method for using thetissue aware properties of the present embodiments in order to tunedetection to match tissue or organ emissivities. Generally, any region,no matter how much radiation it produces, can always be imagedsufficiently simply by leaving the measuring device in position for longenough. However, in many cases there may be limited time available. Forsuch cases in which there is limited time for data acquisition, thepresent embodiments can be used to identify regions that may be expectedto produce less emission. The system may then tune imaging resources orresolution onto those tissues according to the number of photonsavailable. Clearly the more photons obtained the more reliable is thedata, and therefore a tissue aware system is able to concentrate moredetectors on the weaker signaling tissues.

If there are still not enough photons, or there are not enoughdetectors, then another way of pooling resources is to merge neighboringvoxels (or regions). Such a procedure may reduce resolution, but willincrease the overall number of photons for that merged region, and thusenable better classification of that region based on a more reliablephoton count. Such a compromise enables analysis of the same collecteddata by ways that would allow high resolution where there are enoughphotons and lower resolutions where there are less while maintainingreliability of the analysis.

Again the tissue regions may be identified using multiple markers.

The above-described embodiment may lead to controlled sensitivitylevels, currently not available with radioimaging.

The concept of using multiple antibodies can be used for therapypurposes, as in the following:

The specificity of a single antibody carrying a drug (or radioactivetherapy) determines the chance for non-target tissue to receive thedrug, and thus be subject to any toxicity of the drug. In cases wherethere are several antibodies, each with limited specificity, but withaffinity to different ‘background’ tissue, a combination of antibodiesmay be used to improve the overall specificity, and thus to reduceoverall toxicity and enable higher efficacy of treatment.

For example, if a first antibody (A1) based drug binds to the target N1folds its affinity to the closest non-target tissue (B1), and a secondantibody (A2) with similar drug has target affinity which is N2 foldshigher than its closest non-target tissue (B2), then using a mergedtherapy will enable better target vs. non-target specificity, which isbetter than N1 and N2 (assuming B1 and B2 are different).

In a more generalized embodiment, the system may include a signalanalysis module, including a library of patterns that are typical forevery cell type. Each type of cells has one or more patterns associatedwith it, and the pattern determines how a set of markers injectedaccording to a specific protocol (dosage, time, etc) may be expressed inthat cell type. The analysis includes classification of the readingsfrom each voxel based on correlation, or other statistical tools forassessing the most probable tissue classification for each voxel.

Since there may be several cell types for a given disease (e.g. cancermay show in several forms), the algorithm may be optimized to determinethe exact tissue type per voxel or region. Alternatively, the algorithmmay be optimized to determine the general property ofdiseased/non-diseased, while taking the specific classification only asa factor in the statistical analysis.

It should be noted that the system may allow for various protocols foradministering the markers, where injection of the various markers may besimultaneous, or multiple injections at various times, as variousmarkers have different lifetime in the circulation.

The issue of generating imaging using two or more markers is nowconsidered mathematically.

An intensity distribution I, conventionally defined in terms ofradioactive emissions per seconds, is now redefined as a vector ofdistributions over the volume U, forming our input space. Each dimensionof the vector is a different one of the radiopharmaceuticals. Theuniversal set U comprises a set of basic elements u (e.g., pixels in twodimensional spaces, voxels in three dimensional spaces), and I(u) is theintensity in a given basic element u ∈ U. For j radiopharmaceuticalsthis becomes I(u)(j,t) An inverse (or reconstruction) problem ariseswhen one cannot sample directly from I, but can sample from a given setof views Φ. A projection φ∈Φ is defined by the set of probabilities{φ(u):u∈U}, where φ (u) is the probability of detecting a radioactiveemission from a voxel u, as defined by viewing parameters, such as thephysical and geometrical properties of the detecting unit, as well asthe attenuation parameters of the viewed volume U, and the timeparameters. A measurement is obtained by choosing a view φ∈Φ, and thensampling according to the viewing parameters.

For j radiopharmaceuticals or markers and k detectors, the probabilityof seeing a particle becomes φjk (u)

In the following analysis, I is the intensity of a radioactivesubstance, and the viewing parameters include the geometrical propertiesof a collimated detecting unit and the detecting unit's position andorientation with respect to volume U. The number of radioactiveemissions counted by the detecting unit within a time interval is aPoisson distribution, where φ (u) is the detection probability of aphoton emitted from voxel u∈U and the mean of the distribution is theweighted sum Σu∈Uφ(u)I(u).

For the case of the kth detector a measurement Yk=Σu∈UXt(u), where X(U)is a Poisson distribution.

X(j,k,t)(u)=I(i,t)(u)·φ(u)jk(u).

Where Y(j,k,t)=ΣX(j,k,t)(u).

Hence Y(j,k,t))=Poisson(Y(j,k,t))

The projection set is thus defined by a matrix Φ, whose rows are theprojections of the chosen views. I is a vector of densities (specifiedper each element in U), and (ΦI is a vector of respective effectiveintensity levels for the views in the set. A vector of measurements y isobtained by a random sample from each view (according to the associatedPoisson distribution). As discussed above, there are various knownreconstruction methods that provide estimators for I given theprojections Φ and the measurements y.

Using the above mathematics the problem is solved (an image created) oneof the vectors say once an hour. The rates of change are determined.Simultaneously the problem is solved for another of the vectors atsimilar time intervals and the rates of change are determined. Then astage of cross-identification is carried out between the two images, sothat wanted tissues as identified by each image minus unwanted tissuesidentified by each image are concentrated on to form a new image.Cross-identification may be an iterative process.

In the example given above of the imaging of the heart using one bloodmarker and one muscular tissue marker, the areas identified by the bloodmarker are subtracted. The areas identified by the muscle marker areadded, and those tissues not identified by either are likewise ignoredas being signals from outside the target region.

The non-homogenous target area is typically a region of living tissue,generally belonging to a patient. The distinguishable regions within canbe different tissues, different organs, a mixture of blood and organtissue as with the above example of the heart, or tissue regionsexhibiting differential pathologies.

It is expected that during the life of this patent many relevantmarkers, radiological imaging devices and two and three dimensionalimaging systems will be developed and the scopes of the correspondingterms herein, are intended to include all such new technologies apriori.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention, which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination.

Although the invention has been described in conjunction with specificembodiments thereof, it is evident that many alternatives, modificationsand variations will be apparent to those skilled in the art.Accordingly, it is intended to embrace all such alternatives,modifications and variations that fall within the spirit and broad scopeof the appended claims. All publications, patents and patentapplications mentioned in this specification are herein incorporated intheir entirety by reference into the specification, to the same extentas if each individual publication, patent or patent application wasspecifically and individually indicated to be incorporated herein byreference. In addition, citation or identification of any reference inthis application shall not be construed as an admission that suchreference is available as prior art to the present invention.

What is claimed is:
 1. A method of characterizing tissue, comprising:imaging a tissue using a first marker; imaging the tissue using a secondmarker; and characterizing the tissue by analyzing a difference betweenimage data obtained from said imaging using a first marker and imagingusing a second marker.
 2. A method according to claim 1, wherein imaginga tissue comprises generating a series of images of the tissue fromdifferent views.
 3. A method according to claim 1, wherein imaging atissue comprises generating a series of images at different timeintervals.
 4. A method according to claim 1, analyzing a differencebetween image data obtained from said imaging using a first marker andimaging using a second marker comprises superimposing images obtainedfrom said imaging a tissue using a first marker and imaging the tissueusing a second marker.
 5. A method according to claim 1, wherein imaginga tissue using a first marker comprises identifying a region of interestin the tissue and wherein imaging the tissue using a second markercomprises imaging said region of interest.
 6. A method according toclaim 1, analyzing a difference between image data obtained from saidimaging using a first marker and imaging using a second marker comprisesconstraining image date obtained from imaging using a second marker byimage data obtained from imaging using a first marker.
 7. A methodaccording to claim 1, further comprising injecting a patient with saidfirst and second marker simultaneously.
 8. A method according to claim1, further comprising injecting a patient with said first and secondmarker at different times.
 9. A method according to claim 1, whereincharacterizing the tissue comprises identifying if the tissue isdiseased or non-diseased.
 10. A method according to claim 1, whereinanalyzing further classifying the image data of from each voxel based oncorrelation and assessing the most probable tissue classification foreach voxel.
 11. A method according to claim 1, wherein said imaging istuned according to expected photon count from said tissue.
 12. A methodaccording to claim 1, wherein at least one of said first marker andsecond marker is analyzed for its kinetic properties.
 13. A methodaccording to claim 1, further comprising imaging the tissue using atleast one additional marker and wherein said analyzing comprisesanalyzing a difference between image data obtained from said imagingusing a first marker, imaging using a second marker and imaging using atleast one additional marker.
 14. A system for characterizing tissue, theapparatus comprising: a first imager for imaging tissue using a firstmarker; a second imager for imaging tissue using a second marker; and ananalyzing circuit for analyzing image date from said first and secondimager and characterizing the imaged tissue based on said analysis. 15.A system according to claim 14, wherein said first and second imager areadapted to image tissue from different views.
 16. A system according toclaim 14, wherein said analyzing circuit analyzes image data obtained atdifferent time intervals.
 17. A system according to claim 14, whereinsaid analyzing circuit superimposes images obtained from said firstimager and images obtained from said second imager.
 18. A systemaccording to claim 14, wherein said analyzing circuit further analyzesimage data obtainer from said first imager to identify a region ofinterest and wherein said second imager images said region of interest.19. A system according to claim 14, wherein said analyzing circuitconstrains image data obtained from said second imager by image dataobtained from said first imager.
 20. A system according to claim 14,wherein said analyzing circuit identifies if said tissue is diseased ornon-diseased.
 21. A system according to claim 14, wherein the systemfurther comprises a library of patterns for different cell types andwherein said analyzing circuit classifies image data from voxels basedon correlation for assessing a tissue classification for each voxel. 22.A system according to claim 14, wherein said analyzing circuit furthertunes said first and second imager according to expected photon countfrom said tissue.
 23. A system according to claim 14, wherein saidanalyzing comprises analyzing the kinetic properties of at least one ofsaid first and second marker.
 24. A system according to claim 14,further comprising at least one additional imager for imaging tissueusing at least one additional marker and wherein said analyzing circuitanalyzes image date from said first, second and at least one additionalimager.